Compounds with analgesic effect

ABSTRACT

Compounds of general formula (I) ##STR1## wherein m is 0 or 1, and n is 1 or 2; are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to international applicationPCT/SE97/02051, filed on Dec. 9, 1997 and also to Swedish application9604786-5, filed on Dec. 20, 1996.

FIELD OF THE INVENTION

The present invention is related to novel nitrogen ring compounds, to aprocess for their preparation, their use and pharmaceutical compositionscomprising the novel compounds. The novel compounds are useful intherapy, and in particular for the treatment of pain.

BACKGROUND AND PRIOR ART

The δ receptor has been identified as having a role in many bodilyfunctions such as circulatory and pain systems. Ligands for the δreceptor may therefore find potential use as analgesics, and/or asantihypertensive agents. Ligands for the δ receptor have also been shownto possess immunomodulatory activities.

The identification of at least three different populations of opioidreceptors (μ, δ and κ) is now well established and all three areapparent in both central and peripheral nervous systems of many speciesincluding man. Analgesia has been observed in various animal models whenone or more of these receptors has been activated.

With few exceptions, currently available selective opioid δ ligands arepeptidic in nature and are unsuitable for administration by systemicroutes. Some non-peptidic δ antagonists have been available for sometime (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32:239-269. for review). These compounds, e.g. naltrindole, suffer fromrather poor (i.e., <10-fold) selectivity for the δ receptor vs. μreceptor binding and exhibit no analgesic activity, a fact whichunderscores the need for the development of highly selectivenon-peptidic δ ligands.

Thus, the problem underlying the present invention was to find newanalgesics having improved analgesic effects, but also with an improvedside-effect profile over current μ agonists and potential oral efficacy.

Analgesics that have been identified and are existing in the prior arthave many disadvantages in that they suffer from poor pharmacokineticsand are not analgesic when administered by systemic routes. Also, it hasbeen documented that preferred compounds, described within the priorart, show significant convulsive effects when administered systemically.

The problem mentioned above has been solved by developing novelcompounds which possess a piperidine ring, which may be a 5-membered, a6-membered or a 7-membered nitrogen ring, as will be described below.

OUTLINE OF THE INVENTION

The novel compounds according to the present invention are defined bythe general formula (I) ##STR2## wherein m is 0 or 1;

n is 1 or 2;

R¹ is selected from

hydrogen;

a branched or straight C₁ -C₆ alkyl;

C₃ -C₈ cycloalkyl;

C₄ -C₈ (alkyl-cycloalkyl) wherein alkyl is C₁ -C₂ alkyl and cycloalkylis C₃ -C₆ cycloalkyl;

benzyl; ##STR3## where G is a hydroaromatic or a heteroaromatic grouphaving 5 or 6 atoms, and where the heteroatoms are selected from O, Sand N; and ##STR4## and wherein n=0 or 1; C₆ -C₁₀ aryl; or heteroarylhaving from 5 to 10 atoms selected from any of C, S, N and O; whereinthe aryl and heteroaryl may optionally and independently be substitutedby 1 or 2 substituents independently selected from any of hydrogen, CH₃,(CH₂)_(p) CF₃, halogen, CONR⁵ R⁴, COOR⁵, COR⁵, (CH₂)_(p) NR⁵ R⁴,(CH₂)_(p) CH₃ (CH₂)_(p) SOR⁵ R⁴, (CH₂)_(p) SO₂ R⁵, and (CH₂)_(p) SO₂NR⁵, wherein R⁴ and R⁵ is each and independently as defined for R¹ aboveand p is 0, 1 or 2;

(C₁ -C₂ alkyl)-(C₆ -C₁₀ aryl); or (C₁ -C₂ alkyl)heteroaryl, theheteroaryl moieties having from 5 to 10 atoms selected from any of C, S,N and O, and where the aryl or heteroaryl may optionally andindependently be substituted by 1 or 2 substituents independentlyselected from any of hydrogen, CH₃, CONR⁵ R⁴, COOR⁵, COR⁵, (CH₂)_(q) NR⁵R⁴, (CH₂)_(q) CH₃ (CH₂)_(q) SOR⁵ R⁴, (CH₂)_(q) SO₂ R⁵, (CH₂)_(q) SO₂NR⁵, and (CH₂)_(q) OR⁴, wherein

R⁴ and R⁵ is each and independently as defined for R¹ above and q is 0,1 or 2;

A is ##STR5## wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, and R¹⁸ is each and independently as defined for R¹ above andwherein the phenyl ring of each A substituent may be optionally andindependently substituted by 1 or 2 substituents Z¹ and Z² which areeach and independently selected from hydrogen, CH₃, (CH₂)_(r) CF₃,halogen, CONR² R³, CO₂ R², COR², (CH₂)_(r) NR² R³, (CH₂)_(r) CH₃(CH₂)_(r) SOR², (CH₂)_(r) SO₂ R² and (CH₂)_(r) SO₂ NR² R³ wherein R² andR³ is each and independently as defined for R¹ above and wherein r is 0,1, or 2; X is O, S or NR¹⁹ where R¹⁹ is as defined for R¹,

B is a substituted or unsubstituted aromatic, heteroaromatic,hydroaromatic or heterohydroaromatic moiety having from 5 to 10 atomsselected from any of C, S, N and O, optionally and independentlysubstituted by 1 or 2 substituents independently selected from hydrogen,CH₃, (CH₂)_(t) CF₃, halogen, (CH2)_(t) CONR⁵ R⁴, (CH₂)_(t) NR⁵ R⁴,(CH₂)_(t) COR⁵, (CH₂)_(t) COOR⁵, OR⁵, (CH₂)_(t) SOR⁵, (CH₂)_(t) SO₂ R⁵,and (CH₂)tSO₂ NR⁵ R⁴, wherein R⁴ and R⁵ is each and independently asdefined for R¹ above, and t is 0, 1, 2 or 3;

Within the scope of the invention are also pharmaceutically acceptablesalts of the compounds of the formula (I), as well as isomers, hydrates,isoforms and prodrugs thereof.

Preferred compounds according to the invention are compounds of theformula (I) wherein

R¹ is selected from benzyl; ##STR6## where G is a hydroaromatic or aheteroaromatic group having 5 or 6 atoms, and where the heteroatoms areselected from O, S and N; and ##STR7## and wherein n=0 or 1; A isselected from anyone of ##STR8## wherein R⁶, R⁷, R⁸, R⁹, R¹⁶, R¹⁷ andR¹⁸ is each and independently as defined for R¹ above; and Z¹, Z² and Xis each and independently as defined above;

B is selected from phenyl, naphthyl, indolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl,isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl,indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl,tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, andindazolinyl, each optionally and independently substituted by 1 or 2substituents independently selected from hydrogen, CH₃, CF₃, halogen,--(CH₂)_(t) CONR⁵ R⁴, --(CH₂)_(t) NR⁵ R⁴, --(CH₂)_(t) COR⁵, --(CH₂)_(t)CO₂ R⁵, and --OR⁵,

wherein t is 0 or 1, and wherein R⁴ and R⁵ are as defined above.

Especially preferred compounds are compounds of the formula (I) wherein

R¹ is (C₁ -C₂ alkyl)phenyl and hydrogen;

A is ##STR9## wherein R⁶, R⁷, R⁸, R⁹, is each an ethylene group; and Z¹and Z², are as defined above;

B is phenyl or naphtalene; and

m and n is each 1, or m is 1 and n is 0.

The substituents A and B respectively, may optionally be substituted atany position of the ring.

By "halogen" we mean chloro, fluoro, bromo and iodo.

By "aryl" we mean an aromatic ring having from 6 to 10 carbon atoms,such as phenyl and naphtyl.

By "heteroaryl" we mean an aromatic ring in which one or more of thefrom 5-10 atoms in the ring are elements other than carbon, such as N, Sand O.

By "hydroaromatic" we mean a partly or fully saturated aromatic ringstructure having from 5-10 carbon atoms in the ring.

By "heterohydroaromatic" we mean a partly or fully saturated aromaticring structure in which one or more of the from 5-10 atoms in the ringare elements other than carbon, such as N, S and O.

By "isomers" we mean compounds of the formula (I), which differ by theposition of their functional group and/or orientation. By "orientation"we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.

By "isoforms" we mean compounds of the formula (I) which differ by theircrystal lattice, such as crystalline compound and amorphous compounds.

By "prodrug" we mean pharmacologically acceptable derivatives, e.g.esters and amides, such that the resulting biotransformation product ofthe derivative is the active drug. The reference by Goodman and Gilmans,The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int.Ed. 1992, "Biotransformation of Drugs", p. 13-15, describing prodrugsgenerally, is hereby incorporated.

The novel compounds of the present invention are useful in therapy,especially for the treatment of various pain conditions such as chromicpain, acute pain, cancer pain, pain caused by rheumatoid arthritis,migraine, visceral pain etc. This list should however not be interpretedas exhaustive.

Compounds of the invention are useful as immunomodulators, especiallyfor autoimmune diseases, such as arthritis, for skin grafts, organtransplants and similar surgical needs, for collagen diseases, variousallergies, for use as anti tumour agents and anti viral agents.

Compounds of the invention are useful in disease states wheredegeneration or dysfunction of opioid receptors is present or implicatedin that paradigm. This may involve the use of isotopically labelledversions of the compounds of the invention in diagnostic techniques andimaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of diarrhoea,depression, urinary incontinence, various mental illnesses, cough, lungoedema, various gastrointestinal disorders, spinal injury and drugaddiction, including the treatment of alcohol, nicotine, opioid andother drug abuse and for disorders of the sympathetic nervous system forexample hypertension.

Compounds of the invention are useful as an analgesic agent for useduring general anaesthesia and monitored anaesthesia care. Combinationsof agents with different properties are often used to achieve a balanceof effects needed to maintain the anaesthetic state (eg. Amnesia,analgesia, muscle relaxation and sedation). Included in this combinationare inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockersand opioids.

The compounds of the present invention in isotopically labelled form areuseful as a diagnostic agent.

Also within the scope of the invention is the use of any of thecompounds according to the formula (I) above, for the manufacture of amedicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of asubject suffering from any of the conditions discussed above, whereby aneffective amount of a compound according to the formula (I) above, isadministered to a patient in need of such treatment.

METHODS OF PREPARATION

Compounds of the formula (I), as described above, may be obtained by thearylation of an amine of formula (II) ##STR10## wherein R¹, m and n areas defined in formula (I) above, and W is A or B as defined in formula(I) above, by an arylating agent of formula (III)

    W--Z                                                       (III)

wherein W is A or B as defined in formula (I) above, and Z is a suitablesubstituent, i.e. a reactive component suitable to be used in thedefined process, which will be appreciated by a person skilled in theart, preferably halogen, triflate (CF₃ SO₃ --), mesylate (CH₃ SO₃ --),tosylate (CH₃ (C₆ H₄)SO₃ --), tributyltin, triacetoxylead,diarylbismuth, borate (B(OH)₂), cuprate or other such group known in theart. The arylation may be catalyzed by metals, preferably Cu, Ni, Pd orsuitable salts, complexes, oxides or hydroxides thereof. The4-aminopiperidine of formula (II) above may be converted completely orpartially to its corresponding anion by treatment with bases, preferablytriethylamine, 4-dimethyl-aminopyridine, K₂ CO₃, NaOH, NaH, lithiumdiisopropylamide, sodium tert-butoxide or the like, prior or during thearylation process. The reaction may be performed in the presence ofcomplexing reagents, preferably triphenylphosphine, triphenylarsine,dibenzyl-ideneacetone, 2,2'-bis(diphenylphosphino)-1,1'-binaphtyl,1,1'-bis(diphenylphosphino)-ferrocene, oxygen or other such compoundsknown in the art. The reaction may optionally be performed in thepresence of one or more solvents such as toluene, dichloromethane,tetrahydrofuran, dimethylformamide, dioxane, acetonitrile ordimethylsulfoxide, or in solvent mixtures.

R¹ and the substituents on A and B of compound (I) as defined above, maybe modified after or during the preparation of (I) from (II) and (III)by methods known in the art, for example reduction, oxidation andalkylation.

The amine of formula (II) may be prepared by reductive amination of aketone of the formula (IV) ##STR11## wherein R¹, R², R³, m and n are asdefined in formula (I) above, with a substituted arylamine (V)

    W--NH.sub.2                                                (V)

wherein W is as defined in formula (II) above.

The reductive amination may be performed in a one or a two stage processinvolving a Br.o slashed.nstedt or a Lewis acid and a reducing agent.Suitable acids are sulphuric acid, polyphosphoric acid,4-toluenesulphonic acid, titanium iso-propoxide, aluminium trichloride,boron trifluoride diethyl etherate, or the like. Suitable reducingagents are hydrogen in the presence of a catalyst, preferably Pd, Pd--C,Pd(OH)₂, PtO₂, Rh--C or Raney-Nickel, sodium borohydride, sodiumcyanoborohydride, lithium aluminumhydride, diborane,di-iso-butylaluminiumhydride, or the like. The reaction may be performedin the presence of one or more solvents which may be organic orinorganic, such as toluene, dichloromethane, ethers, alcohols, aceticacid, water, or in solvent mixtures.

R¹ and the substituents on W of compound (II), as defined above, may bemodified after or during preparation of (I) from (II) and (III), bymethods known in the art, for example reduction, oxidation andalkylation, after or during the preparation of (II) from (IV) and (V).

Compounds of formula (III), (IV) and (V) may be commercially available,prepared by literature procedures or prepared by methods known in theart.

The invention will now be described in more detail by way of thefollowing examples, which should not in any way be regarded as limitingthe invention.

EXAMPLES Example 1 (i) Preparation of4-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide (compound 1)##STR12##

Ti(Oi-Pr)₄ (14.8 mL, 50 mmol) was added to a mixture of4-amino-(N,N-diethyl)-benzamide (4.81 g, 25 mmol) and1-benzyl-4-piperidone (6.95 mL, 37.5 mmol) at room temperature. Themixture was sonicated at 40° C. for 2 h, and stirred at 60° C. for 15 h.The mixture was cooled in an ice-bath and EtOH (100 mL) and NaBH₄pellets (3.5 g, 91 mmol) were added. After stirring for 1 h at 0° C. and20 h at room temperature, 1M NH₄ OH (50 mL) was added. The mixture wasstirred at room temperature for 30 min, diluted with CH₂ Cl₂

(100 mL) and filtered through a pad of Celite®. The layers in thefiltrate were separated, the aqueous layer extracted with CH₂ Cl₂ (100mL) and the combined organic phases washed with NaHCO₃ (aq., sat., 100mL) and dried over K₂ CO₃. The mixture was filtered, concentrated andthe residue purified by chromatography (gradient, PhMe to Me₂ CO) andcrystallisation (PhMe) to give the title compound 1 (7.48 g, 82%) as abeige solid.

IR (KBr): 3343, 2939, 1608, 1528, 1459, 1422, 1339, 1285, 1174, 1091,981, 827, 735 cm⁻¹.

¹ H NMR (CDCl₃): 7.32 (d, 4H), 7.26 (t, 1H), 7.23 (d, 2H), 6.54 (d, 2H),3.72 (broad s, 1H), 3.53 (s, 2H), 3.42 (broad d, 4H), 3.32 (broad s,1H), 2.84 (d, 2H), 2.15 (t,2H), 2.02 (d, 2H), 1.48 (q, 2H), 1.17 (t,6H).

¹³ C NMR (CDCl₃): 171.7, 148.1, 138.3, 129.1, 128.5, 128.2, 127.0,125.3, 112.2, 63.1, 52,2, 49.8, 41.5 (broad), 32.4, 13.6 (broad).

An analytical sample was prepared by recrystallisation from PhMe.

Anal. calcd. for C₂₃ H₃₁ N₃ O: C, 75.58; H, 8.55; N, 11.50; Found: C,75.58; H, 8.63; N, 11.31.

(ii) Preparation of 4-[N-(1-benzyl-piperidin-4-yl)-anilino]-N,N-diethylbenzamide (compound 2) ##STR13##

A mixture of 4-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide(compound 1) (0.58 g, 1.59 mmol), Ph₃ Bi (0.84 g, 1.90 mmol) andCu(OAc)₂ (0.43 g, 2.38 mmol) in PhMe (25 mL) was heated at 110° C. for15 h. Ph₃ Bi (0.84 g, 1.90 mmol) and Cu(OAc)₂ (0.43 g, 2.38 mmol) wasadded and the mixture was stirred at reflux for 6 h. Ph₃ Bi (0.84 g,1.90 mmol) and Cu(OAc)₂ (0.43 g, 2.38 mmol) was added, the mixturestirred at reflux for 15 h, allowed to cool and quenched with 1M NH₄ OH(5 mL). The mixture was stirred at room temperature for 30 min, dilutedwith EtOAc (25 mL) and filtered through a pad of Celite®. The layers inthe filtrate were separated, the deep blue aqueous layer extracted withEtOAc (25 mL) and the combined organic phases washed with H₂ O (50 mL)and brine (25 mL) and dried over K₂ CO₃. The mixture was filtered,concentrated and the residue purified by chromatography (gradient, PhMeto Me₂ CO) to give the title compound 2 (0.33 g, 47%) as a colorlessoil.

¹ H NMR (CDCl₃): 7.53 (t, 2H), 7.29-7.18 (m, 8H), 7.01 (d, 2H), 6.58 (d,2H), 3.85 (t, 1H), 3.49 (s, 2H), 3.42 (d, 4H), 2.95 (d, 2H), 2.11 (t,2H), 1.92 (d, 2H), 1.51 (q, 2H), 1.17 (t, 6H).

¹³ C NMR (CDCl₃): 171.5, 149.0, 143.6, 138.2, 129.5, 129.1, 128.7,128.2, 128.1, 127.0, 126.7, 125.4, 116.0, 63.1, 55.5, 53.3, 40 (broad),30.7, 13 (broad).

An analytical sample was obtained as a hydrochloride by adding asolution of the free base in ether/EtOH to ice cold diluted etheral HCl.

IR (KBr): 3423, 2975, 2934, 2529, 1606, 1458, 1285, 1094, 750, 705 cm⁻¹.

Anal. calcd. for C₂₉ H₃₅ N₃ O*HCl*H₂ O: C, 70.21; H, 7.72; N, 8.47;Found: C, 70.02; H, 7.61; N, 8.35.

Example 2 Preparation of4-[N-(1-benzyl-piperidin-4-yl)-4-methyl-anilino]-N,N-diethyl benzamide(compound 3) ##STR14##

A mixture of 4-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide(compound 1) (0.37 g, 1.00 mmol), tri-4-tolylbismuth (1.59 g, 3.30 mmol)and Cu(OAc)₂ (0.54 g, 3.00 mmol) in PhMe (20 mL) was heated at refluxfor 16 h. The mixture was allowed to cool and quenched with H₂ O (2 mL).The mixture was stirred for 1 h, diluted with EtOAc (25 mL) and filteredthrough a pad of Celite®. The layers in the filtrate were separated, theaqueous layer extracted with EtOAc (25 mL) and the combined organicphases washed with H₂ O (50 mL) and brine (25 mL) and dried over MgSO₄.The mixture was filtered, concentrated and the residue purified bychromatography (gradient, CH₂ Cl₂ to 8% MeOH/CH₂ Cl₂) to give the titlecompound 3 (0.09 g, 20%) as a colorless oil.

¹ H NMR (CDCl₃): 7.30-7.16 (m, 9H), 6.94 (d, 2H), 6.52 (d, 2H), 3.83 (t,1H), 3.48 (s, 2H), 3.42 (d, 4H), 2.93 (d, 2H), 2.36 (s, 3H), 2.07 (t,2H), 1.90 (d, 2H), 1.50 (q, 2H), 1.16 (t, 6H).

¹³ C NMR (CDCl₃): 171.6, 149.7, 140.4, 138.2, 136.1, 130.2, 130.2,129.0, 128.1, 128.0, 126.9, 125.3, 113.8, 63.0, 55.4, 53.3, 41 (broad),30.5, 21.0, 13 (broad).

An analytical sample was obtained as a hydrochloride by adding anetheral solution of the free base to ice cold diluted etheral HCl.

IR (KBr): 2936, 2528, 1605, 1510, 1457, 1428, 1284, 1094, 952, 742, 701cm⁻¹.

Anal. calcd. for C₃₀ H₃₇ N₃ O*HCl*0.5 H₂ O: C, 71.91; H, 7.84; N, 8.39;Found: C, 71.75; H, 7.83; N, 8.32.

Example 3 Preparation of4-[N-(1-benzyl-piperidin-4-yl)-1-naphtylamino]-N,N-diethyl benzamide(compound 4) ##STR15##

A mixture of 4-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide(compound 1) (0.37 g, 1.00 mmol), tri-1-naphtylbismuth (0.53 g, 1.20mmol) and Cu(OAc)₂ (0.27 g, 1.50 mmol) in PhMe (20 mL) was heated atreflux for 17 h. Tri-1-naphtylbismuth (0.53 g, 1.20 mmol) and Cu(OAc)₂(0.27 g, 1.50 mmol) was added at room temperature. The mixture wasstirred at reflux for 22 h, allowed to cool and quenched with 1M NH₄ OH(5 mL). The mixture was stirred for 30 min, diluted with EtOAc (25 mL)and filtered through a pad of Celite®. The layers in the filtrate wereseparated, the deep blue aqueous layer extracted with EtOAc (25 mL) andthe combined organic phases washed with H₂ O (50 mL) and brine (25 mL)and dried over K₂ CO₃. The mixture was filtered, concentrated and theresidue purified by chromatography (gradient, PhMe to Me₂ CO) to givethe title compound 4 (0.41 g, 83%) as a brownish solid.

IR (KBr): 2939, 2796, 1619, 1511, 1456, 1420, 1346, 1282, 1180, 1099,783 cm⁻¹.

¹ H NMR (CDCl₃): 7.87 (t, 2H), 7.79 (d, 1H), 7.51 (t, 1H), 7.46 (t, 1H),7.37 (t, 1H), 7.31 (d, 1H), 7.28-7.19 (m, 5H), 7.17 (d, 2H), 6.41 (d,2H), 4.08 (t, 1H), 3.46 (s, 2H), 3.40 (d, 4H), 2.89 (d, 2H), 2.11 (t,2H), 2.08 (broad s, 2H), 1.50 (broad s, 2H), 1.14 (t, 6H).

¹³ C NMR (CDCl₃): 171.7, 149.8, 138.9, 138.1, 135.0, 133.4, 129.1,129.0, 128.3, 128.2, 128.1, 128.0, 127.0, 126.4, 126.2, 126.1, 124.6,124.5, 112.2, 63.0, 56.5, 53.3, 40 (broad), 30.4, 13.5 (broad).

An analytical sample was obtained by recrystallization from EtOH

Anal. calcd. for C₃₃ H₃₇ N₃ O: C, 80.61; H, 7.59; N, 8.55; Found: C,80.48; H, 7.41; N, 8.52.

Example 4 Preparation of4-[N-(1-benzyl-piperidin-4-yl)-2-naphtylamino]-N,N-diethyl benzamide(compound 5) ##STR16##

A mixture of 4-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide(compound 1) (0.67 g, 1.83 mmol), tri-2-naphtylbismuth (0.97 g, 2.20mmol) and Cu(OAc)₂ (0.50 g, 2.75 mmol) in PhMe (35 mL) was heated atreflux for 15 h. Tri-2-naphtylbismuth (0.97 g, 2.20 mmol) and Cu(OAc)₂(0.50 g, 2.75 mmol) was added and the mixture was stirred at reflux for22 h. Tri-2-naphtylbismuth (0.97 g, 2.20 mmol) and Cu(OAc)₂ (0.50 g,2.75 mmol) was added. After reflux for 70 h the mixture was allowed tocool and quenched with 1M NH₄ OH (10 mL). The mixture was stirred for 30min, diluted with EtOAc (35 mL) and filtered through a pad of Celite®.The layers in the filtrate were separated, the deep blue aqueous layerextracted with EtOAc (35 mL) and the combined organic phases washed withH₂ O (75 mL) and brine (35 mL) and dried over MgSO₄. The mixture wasfiltered, concentrated and the residue purified by chromatography(gradient, PhMe to Me₂ CO) to give the title compound 5 (0.63 g, 70%) asa brown oil that solidified on standing.

IR (KBr): 2935, 2807, 1614, 1510, 1424, 1284 cm⁻¹.

¹ H NMR (CDCl₃): 7.83-7.78 (m, 2H), 7.74 (d, 1H), 7.48-7.42 (m, 3H),7.27-7.21 (m, 7H), 7.10 (dd, 1H), 6.66 (d, 2H), 3.94 (t, 1H), 3.48 (s,2H), 3.43 (broad s, 4H), 2.94 (d, 2H), 2.14 (t, 2H), 1.99 (s, 2H), 1.57(m, 2H), 1.17 (t, 6H).

¹³ C NMR (CDCl₃): 171.4, 148.8, 141.3, 138.1, 134.2, 131.2, 129.2,129.0, 128.1, 128.0, 127.5, 127.4, 127.2, 126.9, 126.2, 125.4, 125.3,116.8, 63.0, 55.8, 53.3, 41 (broad), 30.7, 13.6 (broad).

An analytical sample was obtained from MeOH.

Anal. calcd. for C₃₃ H₃₇ N₃ O: C, 80.61; H, 7.59; N, 8.55; Found: C,80.35; H, 7.59; N, 8.46.

Example 5 Preparation ofN,N-diethyl-4-(N-piperidin-4-yl-anilino)benzamide (compound 6) ##STR17##

A solution of 4-[N-(1-benzyl-piperidin-4-yl)-anilino]-N,N-diethylbenzamide (compound 2) (1.21 g, 2.74 mmol) in MeOH (25 mL) washydrogenated at 60 psi for 4 d in the presence of a catalytic amount ofPd(OH)₂ on carbon. The mixture was filtered through a pad of Celite®,concentrated and the residue purified by chromatography (gradient, CH₂Cl₂ to CH₂ Cl₂ /MeOH (9:1) to CH₂ Cl₂ /MeOH/NH₄ OH (aq., conc.)(80:18:2) to give the title compound 6 (0.62 g, 64%) as a colorless oil.

¹ H NMR (CDCl₃): 7.37 (t, 2H), 7.25-7.22 (m, 3H), 7.01 (d, 2H), 6.61 (d,2H), 3.98 (t, 1H), 3.42 (broad d, 4H), 3.17 (d, 2H), 2.78 (t, 2H), 2.00(d, 2H), 1.71 (broad s, 1H), 1.41 (q, 2H), 1.18 (t, 6H).

¹³ C NMR (CDCl₃): 171.4, 148.2, 143.1, 129.8, 128.0, 127.9, 127.7,125.7, 116.9, 53.5, 44.4, 41 (broad), 28.7, 13.5 (broad).

An analytical sample was obtained as a hydrochloride by adding anetheral solution of the free base to ice cold diluted etheral HCl.

IR (KBr): 3426, 3359, 2936, 2722, 1603, 1473, 1281, 1091, 708, 503 cm⁻¹.

Anal. calcd. for C₂₂ H₂₉ N₃ O*HCl*H₂ O: C, 65.09; H, 7.95; N, 10.35;Found: C, 65.37; H, 7.94; N, 10.38.

Example 6 Preparation ofN,N-diethyl-4-([N-piperidin-4-yl]-1-naphtylamino benzamide (compound 7)##STR18##

A solution of 4-[N-(1-benzyl-piperidin-4-yl)-1-naphtylamino]-N,N-diethylbenzamide (compound 4) (0.22 g, 0.45 mmol) in EtOH (20 mL) washydrogenated at 60 psi for 64 h in the presence of a catalytic amount ofPd(OH)₂ on carbon. The mixture was filtered through a pad of Celite®,concentrated and the residue purified by chromatography (gradient, CH₂Cl₂ to CH₂ Cl₂ /MeOH (9:1) to CH₂ Cl₂ /MeOH/NH₄ OH (aq., conc.)(80:18:2)) to give the title compound 7 (0.12 g, 67%) as a colorless oilthat solidified on standing.

IR (KBr): 2942, 1609, 1512, 1448, 1280 cm⁻¹.

¹ H NMR (CDCl₃): 7.86 (t, 2H), 7.80 (d, 1H), 7.50 (t, 1H), 7.45 (t, 1H),7.36 (t, 1H), 7.30 (d, 1H), 7.18 (d, 2H), 6.42 (d, 2H), 4.20 (t, 1H),3.40 (broad d, 4H), 3.06 (d, 2H), 2.79-2.63 (m, 3H), 2.03 (broad s, 2H),1.39 (broad s, 2H), 1.14 (t, 6H).

¹³ C NMR (CDCl₃): 171.6, 149.4, 138.7, 134.8, 133.3, 128.7, 128.2,128.1, 127.9, 126.3, 126.1, 126.0, 124.4, 124.2, 112.1, 56.1, 46.0, 41(broad), 31.3, 13.4 (broad).

Anal. calcd. for C₂₆ H₃₁ N₃ O*1.25 H₂ O: C, 73.64; H, 7.96; N, 9.91;Found: C, 73.77; H, 7.54; N, 9.96.

Example 7 Preparation ofN,N-diethyl-4-([N-piperidin-4-yl]-2-naphtylamino benzamide (compound 8)##STR19##

(1-chloroethyl) chloroformate (58 μL, 0.53 mmol) was added to a solutionof 4-[N-(1-benzyl-piperidin-4-yl)-2-naphtylamino]-N,N-diethyl benzamide(compound 5) (105 mg, 0.21 mmol) in dichloroethane (2.5 mL) at roomtemperature. The mixture was heated at reflux for 17 h and was thenallowed to cool to room temperature and concentrated. Methanol (2.5 mL)was added and the mixture was heated at reflux for 2.5 h, allowed tocool and concentrated. The residue was partitioned between CH₂ Cl₂ (10mL) and 1M NH₄ OH (10 mL). The layers were separated and the organicphase was washed with H₂ O (10 mL) and brine (10 mL) and dried over K₂CO₃. The mixture was filtered, concentrated and the the residue purifiedby chromatography (gradient, CH₂ Cl₂ to CH₂ Cl₂ /MeOH/NH₄ OH (aq.,conc.) (85:13.5:1.5) and HPLC (LiChroPrep RP-18, eluation withincreasing amounts of 0.1% TFA/MeCN in 0.1% TFA/H₂ O) to give the titlecompound 8 (30 mg) as the trifluoroacetate.

IR (neat): 3420, 1680, 1600 cm⁻¹.

¹ H NMR (CDCl₃, TFA salt) d: 1.10 (6H, m), 1.78 (2H, m,), 2.10 (2H, m,CH(CH)CH(N)CH(CH)), 3.00 (2H, m, CH(CH)NHCH(CH)), 3.35 (6H, m), 4.15(1H, m,), 6.65 (2H, m), 7.00 (1H, m), 7.20 (2H, m), 7.40 (3H, m), 7.75(3H, m, Ar).

Example 8 Preparation of4-[N-(1-[2-phenylethyl]-piperidin-4-yl)-anilino]-N,N-diethyl-benzamide(compound 9) ##STR20##

(2-bromoethyl)benzene (0. 18 mL, 1.30 mmol) was added with stirring toan ice-cold solution of N,N-diethyl-4-(N-piperidin-4-yl-anilino)benzamide (compound 6) (0.21 g, 0.59 mmol), Et₃ N (0.10 mL, 0.75 mmol)and a catalytic amount of 4-dimethyl-aminopyridine in CH₂ Cl₂ (5 mL).The stirred mixture was allowed to attain room temperature over 5 h,heated at reflux for 16 h, allowed to cool to room temperature, dilutedwith CH₂ Cl₂ (10 mL) and washed with H₂ O (15 mL), brine (15 mL) anddried over K₂ CO₃. The mixture was filtered, concentrated and theresidue purified by chromatography (gradient, PhMe to PhMe/Me₂ CO (1:2))to give the title compound 9 (0.11 g, 40%) as a colorless oil whichsolidified on standing.

IR (KBr): 2928, 1612, 1504, 1437, 1280, 1980, 754 cm⁻¹.

¹ H NMR (CDCl₃): 7.36 (t, 2H), 7.30-7.15 (m, 8H), 7.01 (d, 2H), 6.61 (d,2H), 3.88 (t,1H), 3.42 (broad d, 4H), 3.08 (d, 2H), 2.76 (m, 2H), 2.57(m, 2H), 2.17 (t, 2H), 1.97 (d, 2H), 1.55 (q, 2H), 1.18 (t, 6H).

¹³ C NMR (CDCl₂): 171.5, 149.0, 143.5, 140.3, 129.6, 128.6, 128.6,128.4, 128.1, 126.8, 126.1, 125.4, 116.1, 60.6, 55.5, 53.5, 41 (broad),33.9, 30.7, 13.6 (broad).

Anal. calcd. for C₃₀ H₃₇ N₃ O*0.2 C₃ H₆ O: C, 78.66; H, 8.24; N, 8.99;Found: C, 78.55; H, 7.75; N, 8.91.

Example 9 (i) Preparation of3-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide (compound10) ##STR21##

Ti(Oi-Pr)₄ (0.70 ml, 2.37 mmol) was added to a mixture of3-amino-(N,N-diethyl) benzamide (150 mg, 0.78 mmol) and1-benzyl-4-piperidone (0.18 mL, 0.97 mmol) at room temperature. Themixture was sonicated at 40° C. for 6 h, and stirred at room temperaturefor 15 h. The mixture was cooled in an ice-bath and EtOH (5 mL) andNaBH₄ (75 mg, 1.98 mmol) were added. After stirring for 1 h at 0° C. and2 d at room temperature, 2M NH₄ OH (5 mL) was added. The mixture wasstirred at room temperature for 30 min, diluted with CH₂ Cl₂ (10 mL) andfiltered through Celite®. The layers in the filtrate were separated, theaqueous layer extracted with CH₂ Cl₂ (3×10 mL). The combined organicphases were washed with 10% HCl (2×15 mL). The pH in the combinedaqueous extracts was adjusted to 10 with 2N NaOH, and extracted with CH₂Cl₂ (3×10 mL). The combined organic extracts were dried over Na₂ SO₄,filtered, concentrated and the residue purified by chromatography(9:1:0.1 EtOAc:heptane: Et₃ N) to give the title compound 10 (173 mg,61%) as a pale yellow thick oil.

IR (neat): 3333, 1612 cm⁻¹.

¹ H NMR (CDCl₃): 7.40-7.10 (7H, m), 6.55 (2H, m), 3.50 (4H, m), 3.22(4H, m), 2.80 (2H, m), 2.12 (2H, m), 2.00 (2H, m), 1.43 (2H, m), 1.20(3H, m), 1.05 (3H, m).

¹³ C NMR (CDCl₃): 171.6, 147.1, 138.3, 138.2, 129.1, 129.0, 128.1,126.9, 114.6, 113.8, 110.6, 63.0, 52.2, 49.8, 43.1, 38.9, 32.4, 14.1,12.8.

Anal. calcd. for C₂₃ H₃₁ N₃ O*HCl*2.1 H₂ O: C, 63.07; H, 8.28; N, 9.59;Found: C, 63.19; H, 7.94; N, 9.25.

(ii) Preparation of 3-[N-(1-benzyl-piperidin-4-yl)-anilino]-N,N-diethylbenzamide (compound 11) ##STR22##

A mixture of 3-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide(compound 10) (360 mg, 0.98 mmol), Ph₃ Bi (1.10 g, 2.50 mmol), andCu(OAc)₂ (0.45 g, 2.48 mmol) in toluene (10 mL) was heated at 110° C.for 12 h. Another portion of Cu(OAc)₂ (0.45 g) was added and the mixturewas heated at 110° C. for an additional 12 h and allowed to cool to roomtemperature. Water (10 mL) was added and the mixture filtered throughCelite®. The layers in the filtrate were separated, and the organicphase was washed with water, brine, dried over Na₂ SO₄ and concentrated.Chromatography of the residue (9:1 EtOAc/heptane) gave the titlecompound 11 (255 mg, 59%) as a pale yellow thick oil.

IR (neat): 3056, 3010, 2937, 2810, 1629 cm⁻¹.

¹ H NMR (CDCl₃): 7.40-6.60 (14H, m), 3.80 (1H, m), 3.43 (4H, bs), 3.20(2H, bs), 2.90 (2H, m), 2.05 (2H, m), 1.90 (2H, m), 1.48 (2H, m), 1.20(3H, bs), 1.00 (3H, bs).

¹³ C NMR (CDCl₃): 171.3, 147.3, 144.4, 138.1, 129.3, 129.0, 128.0,126.9, 126.4, 123.9, 119.7, 117.5, 116.5, 62.9, 55.3, 53.2, 43.0, 39.0,30.6, 14.0, 12.7.

Anal. calcd. for C₂₉ H₃₅ N₃ O*1.25HCl*0.5 H₂ O: C, 70.15; H, 7.41; N,8.47; Cl, 8.94; Found: C, 69.69; H, 7.34; N, 8.25; Cl, 8.96.

Example 10 Preparation of N,N-diethyl-3-(N-piperidin-4-yl-anilino)benzamide (compound 12) ##STR23##

A solution of 3-[N-(1-benzyl-piperidin-4-yl)-anilino]-N,N-diethylbenzamide (compound 11) (102 mg, 0.23 mmol) in EtOH (15 mL) washydrogenated at 40 psi in the presence of a catalytic amount of Pd(OH)₂on carbon for 2 h. The mixture was filtered through Celite® andconcentrated. The residue was purified by chromatography (9:1:0.5EtOAc/heptane/Et₃ N) to yield the title compound 12 (50 mg, 81%) as apale yellow viscous oil.

IR: (HCl-salt, neat) 3421, 1597, 1494 cm⁻¹.

¹ H NMR (CDCl₃): 7.80-6.50 (9H, m), 4.00 (1H, m), 3.21 (2H, bs), 3.30(2H, m), 3.20 (2H, bs), 2.90 (2H, m), 2.05 (2H, m), 1.70 (2H, m), 1.17(3H, bs), 1.00 (3H, bs).

¹³ C NMR (CDCl₃): 171.0, 143.7, 140.7, 138.0, 129.5, 129.2, 128.2,124.5, 119.7, 117.9, 116.5, 53.2, 43.1, 41.1, 39.0, 28.7, 14.0, 8.9.

An analytical sample was obtained as a hydrochloride by adding anetheral solution of the free base to ice cold diluted etheral HCl.

Anal. calcd. for C₂₈ H₃₃ N₃ O*HCl*1.3 H₂ O: C, 62.30; H, 8.08; N, 9.91;Found: C, 62.40; H, 7.67; N, 9.80.

Example 11 (i) Preparation of4-[N-(1-benzyl-piperidin-3-yl)-amino]-N,N-diethyl benzamide (Compound13) ##STR24##

Ti(Oi-Pr)₄ (2.2 mL, 7.45 mmol) was added to a mixture of4-amino-N,N-diethyl) benzamide (0.36 g, 1.87 mmol) and1-benzyl-3-piperidone (0.70 g, 3.69 mmol) at room temperature. Themixture was sonicated at 40° C. for 1 h, and stirred at room temperaturefor 15 h. The mixture was cooled in an ice-bath and EtOH (15 mL) andNaBH₄ (0.21 g, 5.55 mmol) were added. After stirring for 16 h at roomtemperature, 2M NH₄ OH (15 mL) was added. The mixture was stirred atroom temperature for 30 min, diluted with CH₂ Cl₂ (10 mL) and filteredthrough a pad of Celite®. The layers in the filtrate were separated, theaqueous layer extracted with CH₂ Cl₂ (3×15 mL). The combined organicphases were washed with 10% HCl (2×20 mL). The pH in the combinedaqueous extracts was adjusted to 10 with 2N NaOH, and extracted with CH₂Cl₂ (3×10 mL). The combined organic extracts were dried over Na₂ SO₄,filtered and concentrated. The residue was purified by chromatography(9: 1:0.1 EtOAc/heptane/Et₃ N) to give the title compound 13 (0.32 g,47%) as a pale yellow thick oil.

IR (neat): 3320, 1736, 1608 cm⁻¹.

¹ H NMR (CDCl₃): 7.20 (7H, m), 6.50 (2H, m), 4.22 (1H, bs), 3.60-3.30(7H, m), 2.60 (1H, m), 2.35 (3H, m), 1.65 (2H, m), 1.50 (2H, m), 1.10(6H, m).

¹³ C NMR (CDCl₃): 171.7, 147.9, 138.1, 128.7, 128.4, 128.1, 126.9,124.9, 112.1, 63.0, 58.6, 53.5, 48.3, 41.4, 28.6, 22.3, 13.4.

Anal. calcd. for C₂₃ H₃₁ N₃ O*HCl*2.1 H₂ O: C, 62.81; H, 8.30; N, 9.55;Found: C, 62.75; H, 7.94; N, 9.63.

(ii) Preparation of 4-[N-(1-benzyl-piperidin-3-yl)-anilino]-N,N-diethylbenzamide compound (14) ##STR25##

A mixture of 4-[N-(1-benzyl-piperidin-3-yl)-amino]-N,N-diethyl benzamide(compound 13) (0.29 mg, 0.79 mmol), Ph₃ Bi (0.87 g, 1.98 mmol), andCu(OAc)₂ (0.36 g, 1.98 mmol) in toluene (5 mL) was heated at 110° C. for12 h and allowed to cool to room temperature. Water (5 mL) was added andthe mixture filtered through Celite®. The layers in the filtrate wereseparated and the organic phase washed with water, brine, dried over Na₂SO₄ and concentrated. Chromatography of the residue (9:1 EtOAc/heptane)gave the title compound 14 (0.24 g, 67%) as a pale yellow viscous oil.

IR (neat): 3056, 3012, 2938, 2800, 1613, 1492 cm⁻¹.

¹ H NMR (CDCl₃): 7.40-7.10 (10H, m), 6.95 (2H, d), 6.55 (2H, d), 4.05(1H, m), 3.45 (2H, s), 3.38 (4H, bs), 3.19 (1H), 2.75 (1H, m), 1.90 (1H,m), 1.80-1.60 (4H, m), 1.12 (6H, m).

An analytical sample was obtained as a hydrochloride by adding anetheral solution of the free base to ice cold diluted etheral HCl.

¹³ C NMR (CDCl₃): 171.4, 148.8, 143.4, 138.2, 129.3, 128.7, 128.6,128.4, 128.0, 127.8, 126.8, 125.3, 123.9, 115.7, 62.9, 57.2, 54.4, 53.2,42(b), 29.8, 25.9, 13.4 (b).

Anal. calcd. for C₂₉ H₃₅ N₃ O*1.25HCl*0.5 H₂ O: C, 70.15; H, 7.41; N,8.47; Found: C, 70.30; H, 7.30; N, 8.43; Cl, 8.34.

Example 12 Preparation of N,N-Diethyl-4-(N-piperidin-3-yl-anilino)benzamide (Compound 15) ##STR26##

A solution of 4-[N-(1-benzyl-piperidin-3-yl)-anilino]-N,N-diethylbenzamide (compound 14) (0.28 g, 0.63 mmol) in EtOH (10 mL) washydrogenated at 30 psi in the presence of a catalytic amount of Pd(OH)₂on carbon for 6 h. The mixture was filtered through Celite®,concentrated and the residue purified by chromatography (gradient, 9:1:0to 9:1:0.5 EtOAc/heptane/Et₃ N) to yield the title compound 15 (80 mg,36%) as a pale yellow viscous oil.

IR:(neat) 3300-3500, 1609, 1464 cm⁻¹.

¹ H NMR (CDCl₃): 7.35 (2H, m), 7.18 (3H, m), 6.95 (2H, m), 6.56 (2H, m),4.30 (1H, bs), 4.0 (1H, m), 3.38 (4H, bs), 2.95 (1H, m), 2.35 (2H, m),1.95 (1H, m), 1.70 (2H, m), 1.15 (2H, m), 1.10 (6H, m).

¹³ C NMR (CDCl₃): 171.3, 148.5, 142.8, 129.3, 128.5, 127.7, 126.4,125.5, 115.4, 54.1, 49.3, 45.4, 44-38(b), 29.9, 25.6, 13.3(b).

Anal. calcd. for C₂₂ H₂₉ N₃ O*HCl*0.4 H₂ O: C, 66.87; H, 7.86; N, 10.63;Found: C, 66.85; H, 7.68; N, 10.44.

Example 13 (i) Preparation of3-[N-(1-benzyl-piperidin-3-yl)-amino]-N,N-diethyl benzamide (compound16) ##STR27##

Ti(Oi-Pr)₄ (6.2 mL, 21.0 mmol) was added to a mixture of3-amino-(N,N-diethyl) benzamide (1.0 g, 5.2 mmol) and1-benzyl-3-piperidone (2.0 g, 10.6 mmol) at room temperature. Themixture was sonicated at 40° C. for 2 h, and stirred at room temperaturefor 16 h. The mixture was cooled in an ice-bath and EtOH (30 mL) andNaBH₄ (0.60 g, 15.9 mmol) were added. After stirring for 16 h at roomtemperature, 2M NH₄ OH (25 mL) was added. The mixture was stirred atroom temperature for 30 min, diluted with CH₂ Cl₂ (25 mL) and filteredthrough a pad of Celite®. The layers in the filtrate were separated andthe aqueous layer extracted with CH₂ Cl₂ (3×25 mL). The combined organicphases were washed with 10% HCl (2×25 mL). The pH in the combinedaqueous extracts was adjusted to 10 with 2N NaOH, and extracted with CH₂Cl₂ (3×25 mL). The combined organic extracts were dried over Na₂ SO₄,filtered and concentrated. The residue was purified by chromatography(9:1:0.1 EtOAc/heptane/Et₃ N) to give the title compound 16 (1.10 g,58%) as a pale yellow viscous oil.

IR (neat): 3327, 1606 1440 cm⁻¹.

¹ H NMR (CDCl₃): 7.40-7.00 (7H, m), 6.60-6.40 (2H, m), 4.20 (1H, bs),3.50 (4H, m), 3.20 (2H, bs), 2.60 (1H, m), 2.40-2.20 (3H, m), 1.70 (2H,m), 1.50 (2H, m), 1.20 (3H, bs), 1.00 (3H, bs).

¹³ C NMR (CDCl₃): 171.4, 146.9, 138.1, 137.9, 128.9, 128.6, 127.9,126.7, 114.1, 113.5, 110.4, 62.8, 58.5, 53.3, 48.3, 42.9, 38.7, 28.6,22.2, 13.9, 12.6.

(ii) Preparation of 3-[N-(1-benzyl-piperidin-3-yl)-anilino]-N,N-diethylbenzamide (compound 17) ##STR28##

A mixture of 3-[N-(1-Benzyl-piperidin-3-yl)-amino]-N,N-diethyl benzamide(compound 16) (0.25 g, 0.68 mmol), Ph₃ Bi (0.75 g, 1.70 mmol), andCu(OAc)₂ (0.31 mg, 1.70 mmol) in toluene (5 mL) was heated at 110° C.for 14 h and allowed to cool to room temperature. Water (5 mL) was addedand the mixture was filtered through Celite®. The layers in the filtratewere separated and the organic phase was washed with water and brine,dried over Na₂ SO₄ and concentrated. Chromatography of the residue (9:1EtOAc/heptane) gave the title compound 17 (0.16 g, 52%) as a pale yellowviscous oil.

IR (neat): 3010, 2930, 1630, 1610 cm⁻¹.

¹ H NMR (CDCl₃): 7.40-6.60 (14H, m), 4.05 (1H, m), 3.45 (4H, bs), 3.18(2H, m), 2.75 (1H, m), 1.90 (1H, m), 1.80-1.60 (4H, m), 1.18 (3H, bs),1.00 (3H, bs).

¹³ C NMR (CDCl₃): 171.3, 147.1, 144.5, 138.3, 138.1, 129.3, 129.1,128.8, 128.1, 126.9, 125.9, 123.7,119.8, 117.8, 116.9, 63.0, 57.5, 54.4,53.2, 43.1, 39.0, 29.9, 25.0, 14.1, 12.8.

Anal. calcd. for C₂₉ H₃₅ N₃ O*1.4HCl*0.5 H₂ O: C, 69.38; H, 7.46; N,8.37; Cl, 9.91; Found: C, 69.11; H, 7.14; N, 8.08; Cl, 10.12.

Example 14 Preparation of N,N-Diethyl-3-(N-piperidin-3-yl-anilino)benzamide (compound 18) ##STR29##

A solution of 3-[N-(1-benzyl-piperidin-3-yl)-anilino]-N,N-diethylbenzamide (compound 17) (50 mg, 0.11 mmol) in EtOH (5 mL) washydrogenated at 30 psi in the presence of a catalytic amount of Pd(OH)₂on carbon for 6 h. The mixture was filtered through Celite®,concentrated and the residue purified by chromatography (gradient, 9:1:0to 9:1:0.5 EtOAc/heptane/Et₃ N) to yield the title compound 18 (15 mg,36%) as a pale yellow viscous oil.

¹ H NMR (CDCl₃): 7.40-6.60 (9H, m), 4.40 (1H, m), 3.60 (2H, m),), 3.40(2H, bs), 3.15 (3H, m), 2.50 (2H, m), 1.80(2H), 1.20 (2H, m), 1.18 (3H,bs), 0.95 (3H, bs).

¹³ C NMR (CDCl₃): 171.2, 146.9, 144.0, 138.0, 129.4, 126.4, 124.3,119.7, 117.8, 116.5, 54.1, 45.1, 43.1, 39.0, 30.0, 14.0, 12.7.

An analytical sample was obtained as a hydrochloride by adding anetheral solution of the free base to ice cold diluted etheral HCl.

IR: (neat) 3412, 1598, 1493 cm⁻¹.

Anal. calcd. for C₂₂ H₂₉ N₃ O*HCl*H₂ O: C, 65.09; H, 7.95; N, 10.35;Found: C, 65.03; H, 7.80; N, 10.02.

Example 15 (i) Preparation of4-[N-(1-benzyl-pyrrolidin-3-yl)-amino]-N,N-diethyl benzamide (compound19) ##STR30##

Ti(Oi-Pr)₄ (3.1 ml, 10.4 mmol) was added to a mixture of4-amino-(N,N-diethyl) benzamide (0.50 g, 2.51 mmol) and1-benzyl-3-pyrrolidone (0.85 mL, 5.30 mmol) at room temperature. Themixture was sonicated at 40° C. for 3 h, and stirred at room temperaturefor 16 h. The mixture was cooled in an ice-bath and EtOH (30 mL) andNaBH₄ (0.30 g, 8.00 mmol) were added. After stirring for 16 h at roomtemperature, 2M NH₄ OH (20 mL) was added. The mixture was stirred atroom temperature for 30 min, diluted with CH₂ Cl₂ (20 mL) and filteredthrough a pad of Celite®. The layers in the filtrate were separated, theaqueous layer extracted with CH₂ Cl₂ (3×20 mL). The combined organicphases were washed with 10% HCl (2×20 mL). The pH in the combinedaqueous extracts was adjusted to 10 with 2N NaOH, and extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts were dried over Na₂ SO₄,filtered, concentrated and the residue purified by chromatography(gradient, 9:1:0.5 to 9:0:1 EtOAc/heptane/Et₃ N) to give the titlecompound 19 (0.40 g, 44%) as a pale yellow viscous oil.

IR (neat): 3322, 1609, 1527, 1455 cm⁻¹.

¹ H NMR (CDCl₃): 7.40-7.10 (7H, m), 6.60-6.40 (2H, m), 4.20 (1H, m),3.95 (1H, m), 3.55 (2H, s), 3.35 (4H, bs), 2.70 (2H, m), 2.50-2.35 (2H,m), 2.25 (1H, m), 1.60 (1H, m), 1.15 (6H, bt).

¹³ C NMR (CDCl₃): 171.4, 148.2, 138.4, 128.5, 128.2, 128.1, 126.7,126.1, 113.8, 112.1, 60.5, 59.9, 52.5, 51.9, 41 (b), 32.2, 13.3.

(ii) Preparation of 4-[N-(1-benzyl-pyrrolidin-3-yl)-anilino]-N,N-diethylbenzamide (compound 20) ##STR31##

A mixture of 4-[N-(1-benzyl-pyrrolidin-3-yl)-amino]-N,N-diethylbenzamide (compound 19) (0.40 g, 1.14 mmol), Ph₃ Bi (1.25 g, 2.84 mmol),and Cu(OAc)₂ (0.52 g, 2.86 mmol) in toluene (10 mL) was heated at 110°C. for 16 h and allowed to cool to room temperature. Water (5 mL) wasadded and the mixture was filtered through Celite®. The filtrate waswashed with water, brine, dried over Na₂ SO₄ and concentrated.Chromatography of the residue (95:5 EtOAc/MeOH) gave the title compound20 (0.19 g, 40%) as a pale yellow viscous oil.

¹ H NMR (CDCl₃): 7.40-7.18 (10H, m), 7.05 (2H, m), 6.70 (2H, m), 4.57(1H, m), 3.60 (1H, bd), 3.40 (5H, m), 2.80 (1H, m), 2.60 (1H, m), 2.58(2H, m), 2.20 (1H, m), 1.90 (1H, m), 1.18 (6H, bs).

¹³ C NMR (CDCl₃): 171.4, 149.3, 145.2, 138.9, 129.4, 128.4, 128.1,128.0, 127.7, 127.2, 126.7, 125.0, 117.1, 60.3, 58.3, 57.8, 53.0, 41(b), 29.5, 13.4.

An analytical sample was obtained as a hydrochloride by adding anetheral solution of the free base to ice cold diluted etheral HCl.

IR (neat): 3430, 1610, 1457 cm⁻¹.

Anal. calcd. for C₂₈ H₃₃ N₃ O*HCl*1.3 H₂ O: C, 68.99; H, 7.24; N, 8.62;Found: C, 68.99; H, 7.57; N, 8.62.

Example 16 Preparation of N,N-diethyl-4-(N-pyrrolidin-3-yl-anilino)benzamide (compound 21) ##STR32##

A mixture of the compound 20 (90 mg, 0.2105 mmol), NH₄ O₂ CH (27 mg,0.4282 mmol) and a catalytic amount of 10% Pd/C in MeOH (5 ml) wasstirred vigorously at rt overnight. The catalyst was removed throughcelite and the filtrate condensed in vacuo to give a crude sample whichwas purified through MPLC (100:0 to 9:1 CH₂ Cl₂ :MeOH(10% TEA) on silicagel 60) to yield the title compound 21 (30 mg, 42%) as a pale yellowthick oil.

IR (HCl salt, film)ν: 3428 (NH), 1607(CONEt₂) cm⁻¹.

¹ H NMR (free amine, 400 MHz, CDCl₃) δ: 1.06 (6H, m, 2×CH₂ CH₃ ), 1.90(1H, m, ArNCHCH(CH)CH₂), 2.30 (1H, m, ArNCHCH(CH)CH₂), 2.58 (2H, m,ArNCHCH₂ CH₂ N), 2.95 (1H, m, NHCH(CH)CH₂), 3.23 (1H, m, NHCH(CH)CH₂),3.40 (4H, bs, 2×CH₂ CH₃), 4.70 (1H, m, ArNCH), 6.68 (2H, m, Ar), 7.02(2H, m, Ar), 7.22 (3H, m, Ar), 7.38 (2H, m, Ar).

¹³ C NMR (free amine, 100 Hz, CDCl₃) d: 13.4, 29.7, 41.9, 54.6, 57.9,59.3, 117.5, 125.5, 127.9, 128.0, 129.7, 144.8, 149.2, 171.2.

Elemental analysis: Calcd. for C₂₁ H₂₉ N₃ OCl₂.1.5H₂ O: C, 57.66; H,7.37; N, 9.61. Found: C, 57.86; H, 7.38; N, 9.03.

Example 17 (i) Preparation of4-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzenesulfonamide(compound 22) ##STR33##

Ti(O-i-Pr)₄ (2.10 mL, 7.10 mmol) was added to a mixture of4-amino-(N,N-diethyl)-benzenesulfonamide (0.81 g, 3.55 mmol) and1-benzyl-4-piperidone (0.99 mL, 5.32 mmol) at room temperature. Themixture was sonicated at 40° C. for 40 min, and stirred at 60° C. for 18h. The dark mixture was cooled in an ice-bath and EtOH (15 mL) followedby NaBH₄ pellets (0.5 g, 13.2 mmol) were added. After stirring for 1 hat 0° C. and 20 h at room temperature, 1M NH₄ OH (5 mL) was added. Themixture was stirred at room temperature for 30 min, diluted with CH₂ Cl₂(25 mL) and filtered through a pad of Celite®. The layers in thefiltrate were separated, the aqueous layer extracted with CH₂ Cl₂ (15mL) and the combined organic phases washed with NaHCO₃ (aq., sat., 25mL) and dried over K₂ CO₃. The mixture was filtered, concentrated andthe residue purified by chromatography (gradient, PhMe to Me₂ CO) togive the title compound 22 (0.91 g, 46%) as a tan solid.

IR (KBr): 2942, 1560, 1520, 1321, 1146, 920 cm⁻¹.

¹ H NMR (CDCl₃): 7.55 (d, 2H), 7.34-7.23 (m, 5H), 6.54 (d, 2H), 4.08 (d,1H), 3.53 (s, 2H), 3.29 (broad s, 1H), 3.17 (q, 4H), 2.85 (d, 2H), 2.16(t, 2H), 2.01 (d, 2H), 1.51 (q, 2H), 1.11 (t, 6H).

¹³ C NMR (CDCl₃): 150.2, 138.2, 129.1, 129.0, 128.2, 127.0, 126,8, 63.0,52.1, 49.6, 41.9, 32.2, 14.1.

(ii) Preparation of 4-[N-(1-benzyl-piperidin-4-yl)-anilino]-N,N-diethylbenzenesulfonamide (compound 23) ##STR34##

A mixture of 4-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethylbenzenesulfonamide (compound 22), (0.44 g, 1.10 mmol), Ph₃ Bi (0.58 g,1.31 mmol) and Cu(OAc)₂ (0.30 g, 1.64 mmol) in PhMe (20 mL) was heatedat reflux for 24 h. Ph₃ Bi (0.58 g, 1.31 mmol) and Cu(OAc)₂ (0.30 g,1.64 mmol) were added. The mixture was stirred at reflux for 24 h andPh₃ Bi (0.58 g, 1.31 mmol) and Cu(OAc)₂ (0.30 g, 1.64 mmol) were added.After reflux for 24 h the mixture was allowed to cool and quenched with1M NH₄ OH (5 mL). The mixture was stirred at room temperature for 30min, diluted with EtOAc (25 mL) and filtered through a pad of Celite®.The layers in the filtrate were separated, the deep blue aqueous layerextracted with EtOAc (25 mL) and the combined organic phases washed withH₂ O (50 mL) and brine (25 mL) and dried over K₂ CO₃. The mixture wasfiltered, concentrated and the residue purified by chromatography(gradient, PhMe to Me₂ CO) to give the title compound 23 (50 mg, 10%) asa brown oil.

¹ H NMR (CDCl₃): 7.51 (d, 2H), 7.43 (t, 2H), 7.35 (t, 1H), 7.30-7.22 (m,5H), 7.07 (d, 2H), 6.48 (d, 2H), 3.86 (t, 1H), 3.48 (s, 2H), 3.18 (q,4H), 2.94 (d, 2H), 2.11 (t, 2H), 1.91 (d, 2H), 1.50 (q, 2H), 1.11 (t,6H).

¹³ C NMR (CDCl₃): 151.8, 141.5, 138.1, 131.1, 129.9, 129.1, 128.6,128.1, 127.5, 127.0, 125.9, 112.7, 63.0, 55.8, 53.1, 42.0, 30.6, 14.2.

Purification with HPLC (LiChroPrep RP-18, eluation with increasingamounts of 0.1% TFA/MeCN in 0.1% TFA/H₂ O) gave an analytical sample asa white solid.

IR (KBr): 3433, 1677, 1586, 1496, 1324, 1196, 1148, 719 cm⁻¹.

Anal. calcd. for C₂₈ H₃₅ N₃ O₂ S*1.25 CF₃ COOH: C, 59.07; H, 5.89; N,6.78; Found: C, 59.00; H, 6.01; N, 7.01.

Example 18 Preparation of N,N-diethyl-4-(N-piperidin-4-yl-anilino)benzenesulfonamide (compound 24) ##STR35##

(1-chloroethyl) chloroformate (10 μL, 0.1 mmol) was added to a solutionof 4-[N-(1-benzyl-piperidin-4-yl)-anilino]-N,N-diethylbenzenesulfonamide (compound 23) (19 mg, 40 μmol) in toluene (1 mL) atroom temperature. The mixture was heated at reflux for 16 h, allowed tocool to room temperature and concentrated. Methanol (1 mL) was added andthe mixture was heated at reflux for 4 h, allowed to cool andconcentrated. The residue was partitioned between CH₂ Cl₂ (5 mL) and 1MNH₄ OH (5 mL). The layers were separated and the organic phase waswashed with H₂ O (5 mL) and brine (5 mL) and dried over K₂ CO₃. Themixture was filtered, concentrated and the residue purified by HPLC(LiChroPrep RP-18, eluation with increasing amounts of 0.1% TFA/MeCN in0.1% TFA/H₂ O) to give the title compound 24 (13 mg, 84%) as thetrifluoroacetate.

IR (KBr): 3420, 1658, 1199, 1146, 714 cm⁻¹.

¹ H NMR (CD₃ OD: δ: 7.66-7.63 (m, 4H), 7.55 (t, 1H), 7.28 (d, 2H), 6.76(d, 2H), 4.50 (t, 1H), 3.54 (d, 2H), 3.35-3.23 (m, 6H), 2.34 (d, 2H),1.73 (q, 2H), 1.19 (t, 6H).

¹³ C NMR (CD₃ OD) δ: 153.4, 142.4, 132.8, 131.7, 130.1, 129.7, 128.8,114.4, 53.6, 45.2, 43.6, 29.2, 14.9.

Anal. calcd. for C₂₈ H₃₅ N₃ O₂ S×2 CF₃ COOH×1.5 H₂ O: C, 46.73; H, 5.33;N, 6.54; Found: C, 46.54; H, 5.01; N, 6.71.

The best mode of performing the invention known at present, is to usethe compounds of Example 1, 2, 3, 4, 5, 6, 7, 17 and 18.

Pharmaceutical Compositions

The novel compounds according to the present invention may beadministered orally, intramuscularly, subcutaneously, topically,intranasally, intraperitoneally, intrathoracially, intravenously,epidurally, intrathecally, intracerebroventricularly and by injectioninto the joints.

A preferred route of administration is orally, intravenously orintramuscularly.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level at the most appropriate for a particularpatient.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Pharmaceutically acceptable salts are acetate, benzenesulfonate,benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glucaptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate mesylate, methylbromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate(embonate), pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, triethiodide, benzathine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine, procaine, aluminium,calcium, lithium, magnesium, potassium, sodium, and zinc.

Preferred pharmaceutically acceptable salts are the hydrochlorides,trifluoroacetates and bitartrates.

The term composition is intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid from compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

Preferably the pharmaceutical compositions is in unit dosage form. Insuch form, the composition is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparations, for example, packeted tablets, capsules, and powdersin vials or ampoules. The unit dosage form can also be a capsule,cachet, or tablet itself, or it can be the appropriate number of any ofthese packaged forms.

BIOLOGICAL EVALUATION A) IN VITRO MODEL

Cell Culture

Human 293S cells expressing cloned human μ, δ, and κ receptors andneomycin resistance were grown in suspension at 37° C. and 5% CO₂ inshaker flasks containing calcium-free DMEM10% FBS, 5% BCS, 0.1% PluronicF-68, and 600 μg/ml geneticin.

Membrane Preparation

Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0,2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 Mstock in ethanol), incubated on ice for 15 min, then homogenized with apolytron for 30 sec. The suspension was spun at 1000 g (max) for 10 minat 4° C. The supernatant was saved on ice and the pellets resuspendedand spun as before. The supernatants from both spins were combined andspun at 46,000 g(max) for 30 min. The pellets were resuspended in coldTris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pelletswere resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dryice/ethanol and stored at -70° C. until use. The protein concentrationswere determined by a modified Lowry assay with SDS.

Binding Assays

Membranes were thawed at 37° C., cooled on ice, passed 3 times through a25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mMMgCl₂, 1 mg/ml BSA (Sigma A-7888), pH 7.4, which was stored at 4° C.after filtration through a 0.22 m filter, and to which had been freshlyadded 5 μg/ml aprotinin, 10 μM bestatin, 10 μM diprotin A, no DTT).Aliquots of 100 μl (for μg protein, see Table 1) were added to iced12×75 mm polypropylene tubes containing 100 μl of the appropriateradioligand (see Table 1) and 100 μl of test peptides at variousconcentrations. Total (TB) and nonspecific (NS) binding were determinedin the absence and presence of 10 μM naloxone respectively. The tubeswere vortexed and incubated at 25° C. for 60-75 min, after which timethe contents are rapidly vacuum-filtered and washed with about 12ml/tube iced wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl₂) through GF/Bfilters (Whatman) presoaked for at least 2 h in 0.1% polyethyleneimine.The radioactivity (dpm) retained on the filters was measured with a betacounter after soaking the filters for at least 12 h in minivialscontaining 6-7 ml scintillation fluid. If the assay is set up in96-place deep well plates, the filtration is over 96-place PEI-soakedunifilters, which were washed with 3×1 ml wash buffer, and dried in anoven at 55° C. for 2 h. The filter plates were counted in a TopCount(Packard) after adding 50 μl MS-20 scintillation fluid/well.

Data Analysis

The specific binding (SB) was calculated as TB-NS, and the SB in thepresence of various test peptides was expressed as percentage of controlSB. Values of IC₅₀ and Hill coefficient (n_(H)) for ligands indisplacing specifically bound radioligand were calculated from logitplots or curve fitting programs such as Ligand, GraphPad Prism,SigmaPlot, or ReceptorFit. Values of K_(i) were calculated from theCheng-Prussoff equation. Mean±S.E.M. values of IC₅₀, K_(i) and n_(H)were reported for ligands tested in at least three displacement curves.

Receptor Saturation Experiments

Radioligand K.sub.δ values were determined by performing the bindingassays on cell membranes with the appropriate radioligands atconcentrations ranging from 0.2 to 5 times the estimated K.sub.δ (up to10 times if amounts of radioligand required are feasable). The specificradioligand binding was expressed as pmole/mg membrane protein. Valuesof K.sub.δ and B_(max) from individual experiments were obtained fromnonlinear fits of specifically bound (B) vs. nM free (F) radioligandfrom individual according to a one-site model.

B) BIOLOGICAL MODEL (IN VIVO MODEL) FREUND'S COMPLETE ADJUVANT (FCA),AND SCIATIC NERVE CUFF INDUCED MECHANO-ALLODYNIA IN RAT

Animals

Male Sprague-Dawley rats (Charles River, St-Constant, Canada) weighing175-200 g at the time of surgery were used. They were housed in groupsof three in rooms thermostatically maintained at 20° C. with a 12:12 hrlight/dark cycle, and with free access to food and water. After arrival,the animals were allowed to acclimatize for at least 2 days beforesurgery. The experiments were approved by the appropriate MedicalEthical Committee for animal studies.

EXPERIMENTAL PROCEDURE FREUND'S COMPLETE ADJUVANT

The rats were first anesthetized in a Halothane chamber after which 10μl of FCA was injected s.c. into the dorsal region of the left foot,between the second and third external digits. The animals were thenallowed to recover from anesthesia under observation in their home cage.

SCIATIC NERVE CUFF

The animals were prepared according to the method described by Mosconiand Kruger (1996). Rats were anesthetized with a mixture ofKetamine/Xylazine i.p. (2 ml/kg) and placed on their right side and anincision made over, and along the axis of, the lateral aspect of theleft femur. The muscles of the upper quadriceps were teased apart toreveal the sciatic nerve on which a plastic cuff (PE-60 tubing, 2 mmlong) was placed around. The wound was then closed in two layers with3-0 vicryl and silk sutures.

DETERMINATION OF MECHANO-ALLODYNIA USING VON FREY TESTING

Testing was performed between 08:00 and 16:00 h using the methoddescribed by Chaplan et al. (1994). Rats were placed in Plexiglas cageson top of a wire mesh bottom which allowed access to the paw, and wereleft to habituate for 10-15 min. The area tested was the mid-plantarleft hind paw, avoiding the less sensitive foot pads. The paw wastouched with a series of 8 Von Frey hairs with logarithmicallyincremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and15.14 grams; Stoelting, Ill., USA). The von Frey hair was applied fromunderneath the mesh floor perpendicular to the plantar surface withsufficient force to cause a slight buckling against the paw, and heldfor approximately 6-8 seconds. A positive response was noted if the pawwas sharply withdrawn. Flinching immediately upon removal of the hairwas also considered a positive response. Ambulation was considered anambiguous response, and in such cases the stimulus was repeated.

TESTING PROTOCOL

The animals were tested on postoperative day 1 for the FCA-treated groupand on post-operative day 7 for the Sciatic Nerve Cuff group. The 50%withdrawal threshold was determined using the up-down method of Dixon(1980). Testing was started with the 2.04 g hair, in the middle of theseries. Stimuli were always presented in a consecutive way, whetherascending or descending. In the absence of a paw withdrawal response tothe initially selected hair, a stronger stimulus was presented; in theevent of paw withdrawal, the next weaker stimulus was chosen. Optimalthreshold calculation by this method requires 6 responses in theimmediate vicinity of the 50% threshold, and counting of these 6responses began when the first change in response occurred, e.g. thethreshold was first crossed. In cases where thresholds fell outside therange of stimuli, values of 15.14 (normal sensitivity) or 0.41(maximally allodynic) were respectively assigned. The resulting patternof positive and negative responses was tabulated using the convention,X=no withdrawal; O=withdrawal, and the 50% withdrawal threshold wasinterpolated using the formula:

    50% g threshold=10.sup.(Xf+kδ) /10,000

where Xf=value of the last von Frey hair used (log units); k=tabularvalue (from Chaplan et al. (1994)) for the pattern of positive/negativeresponses; and δ=mean difference between stimuli (log units). Hereδ=0.224.

Von Frey thresholds were converted to percent of maximum possible effect(% MPE), according to Chaplan et al. 1994. The following equation wasused to compute % MPE: ##EQU1##

ADMINISTRATION OF TEST SUBSTANCE

Rats were injected (subcutaneously, intraperitoneally, or orally) with atest substance prior to von Frey testing, the time betweenadministration of test compound and the von Frey test varied dependingupon the nature of the test compound.

What is claimed is:
 1. A compound of the formula (I) ##STR36## wherein mis 1;n is 1; R¹ is selected fromhydrogen; a branched or straight C₁ -C₆alkyl; C₃ -C₈ cycloalkyl; C₄ -C₈ (alkyl-cycloalkyl) wherein alkyl is C₁-C₂ alkyl and cycloalkyl is C₃ -C₆ cycloalkyl; benzyl; ##STR37## where Gis a hydroaromatic or a heteroaromatic group having 5 or 6 atoms, andwhere the heteroatoms are selected from O, S and N; and ##STR38## andwherein n=0 or 1; C₆ -C₁₀ aryl; or heteroaryl having from 5 to 10 atomsselected from any of C, S, N and O; wherein the aryl and heteroaryl mayoptionally and independently be substituted by 1 or 2 substituentsindependently selected from any of hydrogen, CH₃, (CH₂)_(p) CF₃,halogen, CONR⁵ R⁴, COOR⁵, COR⁵, (CH₂)_(p) NR⁵ R⁴, (CH₂)_(p) CH₃(CH₂)_(p) SOR⁵ R⁴, (CH₂)_(p) SO₂ R⁵, and (CH₂)_(p) SO₂ NR⁵, wherein R⁴and R⁵ is each and independently as defined for R¹ above and p is 0, 1or 2; (C₁ -C₂ alkyl)-(C₆ -C₁₀ aryl); or (C₁ -C₂ alkyl)heteroaryl, theheteroaryl moieties having from 5 to 10 atoms selected from any of C, S,N and O, and where the aryl or heteroaryl may optionally andindependently be substituted by 1 or 2 substituents independentlyselected from any of hydrogen, CH₃, CONR⁵ R⁴, COOR⁵, COR⁵, (CH₂)_(q) NR⁵R⁴, (CH₂)_(q) CH₃ (CH₂)_(q) SOR⁵ R⁴, (CH₂)_(q) SO₂ R⁵, (CH₂)_(q) SO₂NR⁵, and (CH₂)_(q) OR⁴, wherein R⁴ and R⁵ is each and independently asdefined for R¹ above and q is 0, 1 or 2; A is ##STR39## wherein R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ is each andindependently as defined for R¹ above and wherein the phenyl ring ofeach A substituent may be optionally and independently substituted by 1or 2 substituents Z¹ and Z² which are each and independently selectedfrom hydrogen, CH₃, (CH₂)_(r) CF₃, halogen, CONR² R³, CO₂ R², COR²,(CH₂)_(r) NR² R³, (CH₂)_(r) CH₃ (CH₂)_(r) SOR², (CH₂)_(r) SO₂ R² and(CH₂)_(r) SO₂ NR² R³ wherein R² and R³ is each and independently asdefined for R¹ above and wherein r is 0, 1, or 2; X is O, S or NR¹⁹where R¹⁹ is as defined for R¹, B is a substituted or unsubstitutedaromatic, heteroaromatic, hydroaromatic or heterohydroaromatic moietyhaving from 5 to 10 atoms selected from any of C, S, N and O, optionallyand independently substituted by 1 or 2 substituents independentlyselected from hydrogen, CH₃, (CH₂)_(t) CF₃, halogen, (CH₂)_(t) CONR⁵ R⁴,(CH₂)_(t) NR⁵ R⁴, (CH₂)_(t) COR⁵, (CH₂)_(t) COOR⁵, OR⁵, (CH₂)_(t) SOR⁵,(CH₂)_(t) SO₂ R⁵, and (CH₂)tSO₂ NR⁵ R⁴, wherein R⁴ and R⁵ is each andindependently as defined for R¹ ; and t is 0, 1, 2 or 3;as well aspharmaceutically acceptable salts of the compounds of the formula (I),and isomers, hydrates, isoforms and prodrugs thereof.
 2. A compoundaccording to claim 1, whereinR¹ is selected from benzyl; ##STR40## whereG is a hydroaromatic or a heteroaromatic group having 5 or 6 atoms, andwhere the heteroatoms are selected from O, S and N; and ##STR41## andwherein n=0 or 1; A is selected from anyone of ##STR42## wherein R⁶, R⁷,R⁸, R⁹, R¹⁶, R¹⁷ and R¹⁸ is each and independently as defined for R¹above; and Z¹, Z² and X is each and independently as defined above; B isselected from phenyl, naphthyl, indolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl,isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl,indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl,tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, andindazolinyl, each optionally and independently substituted by 1 or 2substituents independently selected from hydrogen, CH₃, CF₃, halogen,--(CH₂)_(t) CONR⁵ R⁴, --(CH₂)_(t) NR⁵ R⁴, --(CH₂)_(t) COR⁵, --(CH₂)_(t)CO₂ R⁵, and --OR⁵,wherein t is 0 or 1, and wherein R⁴ and R⁵ are asdefined for R¹.
 3. A compound according to claim 2, whereinR¹ is (C₁ -C₂alkyl)phenyl and hydrogen; A is ##STR43## wherein R⁶, R⁷, R⁸, R⁹, iseach an ethylene group; and Z¹ and Z², are as defined above; B is phenylor naphtalene; and m and n is each 1, or m is 1 and n is
 0. 4. Acompound, selected from any of ##STR44##
 5. A compound according toclaim 1 in form of its hydrochloride, bitartrate or trifluoroacetatesalt.
 6. A compound according to claim 1, wherein A is: and R⁶, R⁷, Z¹,and Z² are as defined in claim
 1. 7. The compound of claim 6, wherein Z¹and Z² are both hydrogen.
 8. The compound of claim 7, wherein R⁶ and R⁷are both branched or straight C₁ -C₆ alkyls.
 9. The compound of claim 8,wherein R⁶ and R⁷ are straight C₁ -C₃ alkyls.
 10. The compound of claim9, wherein R⁶ and R⁷ are each ethyls.
 11. The compound of any one ofclaims 1, 2, 5, or 6-10, wherein B is an aromatic optionally andindependently substituted by 1 or 2 substituents independently selectedfrom hydrogen, CH₃ (CH₂)_(t) CF₃, halogen, (CH₂)_(t) CONR⁵ R⁴, (CH₂)_(t)NR⁵ R⁴, (CH₂)_(t) COR⁵, (CH₂)_(t) COOR⁵, OR⁵, (CH₂)_(t) SOR⁵, (CH₂)_(t)SO₂ R⁵, and (CH₂)_(t) SO₂ NR⁵ R⁴, wherein R⁴ and R⁵ are each andindependently as defined for R¹ ; and t is 0, 1, 2, or
 3. 12. Thecompound of claim 11, wherein B is a phenyl optionally substituted withone or two substituents each and independently selected from hydrogen,CH₃ (CH₂)_(t) CF₃, halogen, (CH₂)_(t) CONR⁵ R⁴, (CH₂)_(t) NR⁵ R⁴,(CH₂)_(t) COR⁵, (CH₂)_(t) COOR⁵, OR⁵, (CH₂)_(t) SOR⁵, (CH₂)_(t) SO₂ R⁵,and (CH₂)_(t) SO₂ NR⁵ R⁴, wherein R⁴ and R⁵ are each and independentlyas defined for R¹ ; and t is 0, 1, 2, or
 3. 13. The compound of claim12, wherein B has one substituent.
 14. The compound of claim 12, whereinB has two substituents.
 15. A compound of the formula (I) ##STR45##wherein: m is 0;n is 1; R¹ is selected fromhydrogen; a branched orstraight C₁ -C₆ alkyl; C₃ -C₈ cycloalkyl; C₄ -C₈ (alkyl-cycloalkyl)wherein alkyl is C₁ -C₂ and cycloalkyl is C₃ -C₆ cycloalkyl; benzyl;##STR46## wherein G is a hydroaromatic or a heteroaromatic group having5 or 6 atoms, and where the heteroatoms are selected from O, S and N;and ##STR47## wherein n=0 or 1; C₆ -C₁₀ aryl; or heteroaryl having from5 to 10 atoms selected from any of C, S, N and O; wherein the aryl andheteroaryl may optionally and independently be substituted by 1 or 2substituents independently selected from any of hydrogen, CH₃, (CH₂)_(p)CF₃, halogen, CONR⁵ R⁴, COOR⁵, COR⁵, (CH₂)_(p) NR⁵ R⁴, (CH₂)_(p) CH₃(CH₂)_(p) SOR⁵ R⁴, (CH₂)_(p) SO₂ R⁵, and (CH₂)_(p) SO₂ NR⁵, wherein R⁴and R⁵ is each and independently as defmed for R¹ above and p is 0, 1 or2; (C₁ -C₂ alkyl)-(C₆ -C₁₀ aryl); or (C₁ -C₂ alkyl)heteroaryl, theheteroaryl moieties having from 5 to 10 atoms selected from any of C, S,N and O, and where the aryl or heteroaryl may optionally andindependently be substituted by 1 or 2 substituents independentlyselected from any of hydrogen, CH₃, CONR⁵ R⁴, COOR⁵, COR⁵, (CH₂)_(q) NR⁵R⁴, (CH₂)_(q) CH₃ (CH₂)_(q) SOR⁵ R⁴, (CH₂)_(q) SO₂ NR⁵, and (CH₂)_(q)OR⁴, wherein R⁴ and R⁵ is each and independently as defined for R¹ aboveand q is 0, 1 or 2; A is: ##STR48## wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are each and independently asdefined for R¹ above and wherein the phenyl ring of each A substituentmay be optionally and independently be substituted by 1 or 2substituents, Z¹ and Z², which are each independently selected fromhydrogen, CH₃ (CH₂)_(r) CF₃, halogen, CONR² R³, CO₂ R², COR², (CH₂)_(r)NR² R³, (CH₂)_(r) CH₃ (CH₂)_(r) SOR², (CH₂)_(r) SO₂ R² and (CH₂)_(r) SO₂NR² R³, wherein R² and R³ are each independently as defined for R1 aboveand wherein r is 0, 1, or 2; X is O, S or NR¹⁹ where R¹⁹ is as definedfor R¹, B is a substituted or unsubstituted aromatic, heteroaromatic,hydroaromatic or heterohydroaromatic moiety having from 5 to 10 atomsselected from any of C, S, N and O, optionally and independentlysubstituted by 1 or 2 substituents independently selected from hydrogen,CH₃ (CH₂)_(t) CF₃, halogen, (CH₂)_(t) CONR⁵ R⁴, (CH₂)_(t) NR⁵ R⁴,(CH₂)_(t) COR⁵, (CH₂)_(t) COOR⁵, OR⁵, (CH₂)_(t) SOR⁵, (CH₂)_(t) SO₂ R⁵,and (CH₂)_(t) SO₂ NR⁵ R⁴, wherein R⁴ and R⁵ are each independently asdefined for R¹ ; and t is 0, 1, 2 or 3;as well as pharmaceuticallyacceptable salts of the compounds of the formula (I), and isomers,hydrates, isoforms and prodrugs thereof.
 16. A compound according toclaim 15, whereinR¹ is selected from benzyl; ##STR49## where G is ahydroaromatic or a heteroaromatic group having 5 or 6 atoms, and whereinthe heteroatoms are selected from O, S and N; and ##STR50## and whereinn=0 or 1; A is selected from any one of: ##STR51## wherein R⁶, R⁷, R⁸,R⁹, R¹⁶, R¹⁷ and R¹⁸ are each independently as defined for R¹ above; andZ¹, Z² and X are each independently as defined above; B is selected fromphenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl,cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl,tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl,tetrahydrofuranyl, pyrrolidinyl, and indazonlinyl, each optionally andindependently substituted by 1 or 2 substituents independently selectedfrom hydrogen, CH₃, CF₃, halogen, --(CH₂)_(t) CONR⁵ R⁴, --(CH₂)_(t) NR⁵R⁴, --(CH₂)_(t) COR⁵, --(CH₂)_(t) CO₂ R⁵, and --OR⁵, wherein t is 0 or1, and wherein R⁴ and R⁵ are as defined for R¹.
 17. A compound accordingto claim 16, whereinR¹ is (C₁ -C₂ alkyl)phenyl and hydrogen; A is##STR52## wherein R⁶, R⁷, R⁸, R⁹, is each an ethylene group; and Z¹ andZ², are as defined above; B is phenyl or naphthalene; and m and n iseach 1, or m is 1 and n is
 0. 18. The compound of claim 15, in the formof its hydrochloride, bitartrate or trifluoroacetate salt.
 19. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to any one of claims 1-5 as an activeingredient, together with a pharmacologically and pharmaceuticallyacceptable carrier.
 20. A method of treating a patient for pain,comprising administering a compound according to any one of claims 1-5to said patient at a dosage sufficient to reduce or eliminate said pain.21. A method of treating a patient for a gastrointestinal disorder,comprising administering a compound according to any one of claims 1-5to said patient at a dosage sufficient to reduce or eliminate one ormore symptoms associated with said gastrointestinal disorder.
 22. Amethod of treating a patient for a spinal injury, comprisingadministering a compound according to any one of claims 1-5 to saidpatient at a dosage sufficient to reduce one or more symptoms associatedwith said spinal injury.
 23. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 15 asan active ingredient, together with a pharmacologically andpharmaceutically acceptable carrier.
 24. A method of treating a patientfor pain, comprising administering a compound according to any one ofclaims 15-18 to said patient at a dosage sufficient to reduce oreliminate said pain.
 25. A method of treating a patient for agastrointestinal disorder, comprising administering a compound accordingto any one of claims 15-18 to said patient at a dosage sufficient toreduce or eliminate one or more symptoms associated with saidgastrointestinal disorder.
 26. A method of treating a patient for aspinal injury, comprising administering a compound according to any oneof claims 15-18 to said patient at a dosage sufficient to reduce one ormore symptoms associated with said spinal injury.
 27. A process for thepreparation of a compound according to claim 1, comprising:(i)subjecting a ketone of the formula (IV) ##STR53## wherein R¹, m and nare as defined in formula (I) of claim 1 to reductive amination with asubstituted arylamine of the formula (V)

    W--NH.sub.2                                                (V)

wherein W is as defined in formula (I) of claim 1, optionally in thepresence of a solvent, giving a compound of the formula (II) ##STR54##wherein R¹, m and n are as defined in formula (I) above, and W is A or Bas defined in formula (I) above: (ii) optionally modifying R¹ and W informula (II) after or during preparation of (II) from (IV) and (V);(iii) reacting the compound of formula (II) produced in step (i) with anarylating agent of the formula (III)wherein W is A or B as defined informula (I) above, and Z is a suitable substituent, optionally in thepresence of a catalyst to give a compound of the formula (I) of claim 1;and (iv) optionally further modifying R¹, and the substituents on A andB.
 28. A process for the preparation of a compound according to claim15, comprising:(i) subjecting a ketone of the formula (IV) ##STR55##wherein R¹, m and n are as defined in claim 15, to reductive aminationwith a substituted arylamine of the formula (V)

    W--NH.sub.2                                                (V)

optionally in the presence of a solvent, giving a compound of theformula (II) ##STR56## wherein R¹, m and n are as defined above, and Wis A or B as defmed in claim 15; (ii) optionally modifying R¹ and W informula (II) after or during preparation of (II) from (IV) and (V);(iii) reacting the compound of formula (II) produced in step (i) with anarylating agent of formula (III)

    W--Z                                                       (III)

wherein W is A or B as defined in formula (I) above, and Z is a suitablesubstituent, optionally in the presence of a catalyst to give a compoundof the formula (I) of claim 15; and (iv) optionally further modifyingR¹, and the substituents on A and B.